{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T23:08:19Z","timestamp":1794092899044,"version":"4.8.0"},"reference-count":72,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T00:00:00Z","timestamp":1615248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"National Institute for Health","award":["P30-AG062422"],"award-info":[{"award-number":["P30-AG062422"]}]},{"name":"Alzheimer\u2019s Disease Research Center","award":["P01-AG019724"],"award-info":[{"award-number":["P01-AG019724"]}]},{"name":"Alzheimer\u2019s Disease Research Center","award":["K99 AG065501"],"award-info":[{"award-number":["K99 AG065501"]}]},{"name":"Alzheimer\u2019s Disease Research Center","award":["R01 AG045611"],"award-info":[{"award-number":["R01 AG045611"]}]},{"name":"Alzheimer\u2019s Disease Research Center","award":["AG045333"],"award-info":[{"award-number":["AG045333"]}]},{"name":"Alzheimer\u2019s Disease Research Center","award":["K08-AG052648"],"award-info":[{"award-number":["K08-AG052648"]}]},{"name":"Alzheimer\u2019s Disease Research Center","award":["K08-NS114170"],"award-info":[{"award-number":["K08-NS114170"]}]},{"name":"Alzheimer\u2019s Disease Research Center","award":["K24AG053435"],"award-info":[{"award-number":["K24AG053435"]}]},{"name":"Alzheimer\u2019s Disease Research Center","award":["U01 AG057195"],"award-info":[{"award-number":["U01 AG057195"]}]},{"name":"Alzheimer\u2019s Disease Research Center","award":["U54 NS100717"],"award-info":[{"award-number":["U54 NS100717"]}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,8,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Co-pathologies play an important role in the expression of the Alzheimer\u2019s disease clinical phenotype and may influence treatment efficacy. Early-onset Alzheimer\u2019s disease, defined as manifesting before age 65, is viewed as a relatively pure form of Alzheimer\u2019s disease with a more homogeneous neuropathological substrate. We sought to compare the frequency of common neuropathological diagnoses in a consecutive autopsy series of 96 patients with early-onset Alzheimer\u2019s disease (median age of onset = 55\u2009years, 44 females) and 48 with late-onset Alzheimer\u2019s disease (median age of onset = 73\u2009years, 14 females). The UCSF Neurodegenerative Disease Brain Bank database was reviewed to identify patients with a primary pathological diagnosis of Alzheimer\u2019s disease. Prevalence and stage of Lewy body disease, limbic age-related TDP-43 encephalopathy (LATE), argyrophilic grain disease, hippocampal sclerosis, cerebral amyloid angiopathy, and vascular brain injury were compared between the two cohorts. We found at least one non-Alzheimer\u2019s disease pathological diagnosis in 98% of patients with early-onset Alzheimer\u2019s disease (versus 100% of late onset), and the number of comorbid diagnoses per patient was lower in early-onset than in late-onset Alzheimer\u2019s disease (median\u2009=\u20092 versus 3, Mann-Whitney Z\u2009=\u20093.00, P\u2009=\u20090.002). Lewy body disease and cerebral amyloid angiopathy were common in both early and late onset Alzheimer\u2019s disease (cerebral amyloid angiopathy: 86% versus 79%, Fisher exact P\u2009=\u20090.33; Lewy body disease: 49% versus 42%, P\u2009=\u20090.48, respectively), although amygdala-predominant Lewy body disease was more common in early than late onset Alzheimer\u2019s disease (22% versus 6%, P\u2009=\u20090.02). In contrast, LATE (35% versus 8%, P\u2009&amp;lt;\u20090.001), hippocampal sclerosis (15% versus 3%, P\u2009=\u20090.02), argyrophilic grain disease (58% versus 41%, P\u2009=\u20090.052), and vascular brain injury (65% versus 39%, P\u2009=\u20090.004) were more common in late than in early onset Alzheimer\u2019s disease, respectively. The number of co-pathologies predicted worse cognitive performance at the time of death on Mini-Mental State Examination [1.4 points\/pathology (95% confidence interval, CI \u22122.5 to \u22120.2) and Clinical Dementia Rating-Sum of Boxes (1.15 point\/pathology, 95% CI 0.45 to 1.84)], across early and late onset cohorts. The effect of sex on the number of co-pathologies was not significant (P\u2009=\u20090.17). Prevalence of at least one APOE \u03b54 allele was similar across the two cohorts (52% and 54%) and was associated with a greater number of co-pathologies (+0.40, 95% CI 0.01 to 0.79, P\u2009=\u20090.047), independent of age of symptom onset, sex, and disease duration. Females showed higher density of neurofibrillary tangles compared to males, controlling for age of onset, APOE \u03b54, and disease duration. Our findings suggest that non-Alzheimer\u2019s disease pathological diagnoses play an important role in the clinical phenotype of early onset Alzheimer\u2019s disease with potentially significant implications for clinical practice and clinical trials design.<\/jats:p>","DOI":"10.1093\/brain\/awab099","type":"journal-article","created":{"date-parts":[[2021,3,6]],"date-time":"2021-03-06T07:10:24Z","timestamp":1615014624000},"page":"2186-2198","source":"Crossref","is-referenced-by-count":291,"title":["Comorbid neuropathological diagnoses in early versus late-onset Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3570-9143","authenticated-orcid":false,"given":"Salvatore","family":"Spina","sequence":"first","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2581-8100","authenticated-orcid":false,"given":"Renaud","family":"La Joie","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathrine","family":"Petersen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber L","family":"Nolan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deion","family":"Cuevas","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celica","family":"Cosme","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mackenzie","family":"Hepker","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Hye","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5991-3053","authenticated-orcid":false,"given":"Zachary A","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5381-3801","authenticated-orcid":false,"given":"Eric J","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M","family":"Karydas","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harli","family":"Grant","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam L","family":"Boxer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Luisa","family":"Gorno-Tempini","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard J","family":"Rosen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel H","family":"Kramer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce L","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William W","family":"Seeley","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"},{"name":"Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gil D","family":"Rabinovici","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"},{"name":"Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6809-0618","authenticated-orcid":false,"given":"Lea T","family":"Grinberg","sequence":"additional","affiliation":[{"name":"Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA"},{"name":"Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,9]]},"reference":[{"key":"2021101015130333400_awab099-B1","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1001\/jamaneurol.2020.1741","article-title":"Prevalence and clinical phenotype of quadruple misfolded proteins in older adults","volume":"77","author":"Karanth","year":"2020","journal-title":"JAMA 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